EP2531520B1 - Peptidomimétiques fixés au brin matrice ayant une activité modulatrice des cxcr7 - Google Patents

Peptidomimétiques fixés au brin matrice ayant une activité modulatrice des cxcr7 Download PDF

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EP2531520B1
EP2531520B1 EP11702229.3A EP11702229A EP2531520B1 EP 2531520 B1 EP2531520 B1 EP 2531520B1 EP 11702229 A EP11702229 A EP 11702229A EP 2531520 B1 EP2531520 B1 EP 2531520B1
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pro
arg
trp
orn
dab
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EP2531520A1 (fr
Inventor
Frank Otto Gombert
Alexander Lederer
Ralf LÖWE
Daniel Obrecht
Barbara Romagnoli
Johann Zimmermann
Kalpana Patel
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Spexis AG
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Polyphor AG
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Definitions

  • the present invention provides novel peptidomimetics incorporating a chain of ⁇ -amino acid residues as defined below attached to a template which provides specific structural constrains for a ⁇ -hairpin like conformation.
  • These template-fixed ⁇ -hairpin mimetics have a selective modulating activity on the CXCR7 receptor and are thus useful in the treatment of a variety of diseases and disorders mediated by or sustained through the activity of CXCR7 or in the support of therapeutic treatments of specific disease conditions of primarily different cause.
  • the present invention relates to methods of using these compounds in the treatment of the various diseases and disorders, to pharmaceutical compositions and forms comprising these compounds and efficient processes for the preparation and production of these compounds and their intermediates.
  • chemokines and their receptors are mediated by signal transduction that involves chemokines and their receptors, for instance the tissue specific recruitment of leukocytes to sites of inflammation.
  • GPCRs for some receptors the full scope of downstream activity and sometimes organ specific function still remains not fully understood.
  • One of this recently deorphanized GPCRs is the chemokine receptor CXCR7 (RDC1), which binds with high affinity the inflammatory and homing chemokines CXCL11 (ITAC) and CXCL12 (SDF-1) ( K. Balabanian, B. Lagane et al., J. Biol. Chem. 2005, 280, 35760-35766 ).
  • CXCL12 also binds to another chemokine receptor, CXCR4, and the CXCL12/CXCR4 axis has been demonstrated to play a crucial role in different inflammatory and cancer diseases.
  • CXCR4 chemokine receptor 4
  • CXCR7 chemokine receptor 7
  • CXCR7 does not induce typical chemokine responses such as calcium mobilization. Instead, recent findings indicate that the receptor has a key function in the generation of a CXCL12 local gradient for CXCR4-dependent migration by scavenging CXCL12. These observations seem to be in favor of a main role of CXCR7 as a decoy receptor ("CXCL12 sink") with the critical function of clearing excess CXCL12 by internalization ( B. Boldajipour, H. Mahabaleshwar et al., Cell 2008, 132, 463-73 ; Cell Adh. Migr. 2008, 2, 69-70 ).
  • CXCR7 can modulate CXCR4 activity by forming heterodimers and that it may activate other intracellular signaling pathways ( A. Levoye, K. Balabanian et al., Blood 2009,113, 6085-93 ).
  • CXCR7 may be involved in the same disease conditions in which CXCR4 has been shown to play an important role.
  • CXCR7 is markedly expressed in a variety of tumors and their respective tumor cell lines (e.g. prostate, bladder, breast cancer, multiple myeloma, rhabdomyosarcoma, non-small cell lung cancer); its expression level is often correlated with tumor growth and, moreover, with invasiveness.
  • tumors and their respective tumor cell lines e.g. prostate, bladder, breast cancer, multiple myeloma, rhabdomyosarcoma, non-small cell lung cancer
  • CXCR7 Two major mechanisms have been suggested for the role of CXCR7 in tumor development and metastasis: 1) increase of cancer cell proliferation and survival, which may be supported by a pro-angiogenic effect; 2) CXCR7 favors adhesion and transendothelial migration of cancer cells together with CXCR4-mediated migration.
  • CXCR7 may also be implicated in rheumatoid arthritis, other chronic and/or autoimmune inflammatory diseases ( G. Graham et al., Curr. Mol. Med. 2009, 9 (2), 86-93 ) or pulmonary arterial hypertension since it is up-regulated in certain specific tissues, such as in lungs under hypoxic conditions ( C. M. Costello, P. McLoughlin et al., Am. J. Physiol. Lung Cell Mol. Physiol. 2008, 295 (2), 272-284 ).
  • the present invention provides new chemical entities for a potential use as potent, selective and drugable ligands for the GPC-receptor CXCR7.
  • a special strategy is utilized to stabilize ⁇ -hairpin conformations in backbone-cyclic ⁇ -hairpin mimetics exhibiting selective activity against the CXCR7 receptor. This involves transplanting a loop sequence of a natural or unnatural biopolymer onto a template, whose function is to restrain the peptide loop backbone into a ⁇ -hairpin geometry.
  • the present invention relates to novel ⁇ -hairpin peptidomimetics of the general formula (I)
  • alkyl taken alone or in combinations (i.e. as part of another group, such as “arylalkyl”) designates saturated, straight-chain or branched hydrocarbon radicals having up to 12, preferably up to 8, carbon atoms and may be optionally substituted.
  • alkyl is "lower alkyl” which designated alkyl groups having up to 6 carbon atoms.
  • alkenyl taken alone or in combinations, designates straight chain or branched hydrocarbon radicals having up to 12, preferably up to 8, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds. Such alkenyl moieties are optionally substituted and can exist as E or Z configurations, both of which are part of the invention.
  • cycloalkyl taken alone or in combinations, refers to a saturated or partially unsaturated alicyclic moiety having from three to ten carbon atoms and may be optionally substituted. Examples of this moiety include, but are not limited to, cyclohexyl, norbonyl, decalinyl and the like.
  • heterocycloalkyl taken alone or in combinations, describes a saturated or partially unsaturated mono- or bicyclic moiety having from three to nine ring carbon atoms and one or more ring heteroatoms selected from nitrogen, oxygen or sulphur.
  • This term includes, for example, morpholino, piperazino, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, octahydro-1 H -indolyl, 1,7-diazaspiro[4.4]nonane and the like.
  • Said heterocycloalkyl ring(s) may be optionally substituted.
  • aryl taken alone or in combinations, designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be optionally substituted by up to three substituents such as Br, Cl, F, CF 3 , OCF 3 , OCHF 2 , N(CH 3 ) 2 , NO 2 , lower alkyl, lower alkenyl, phenyl or phenoxy.
  • heteroaryl taken alone or in combinations, designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to four heteroatoms selected from the group consisting of O, S and N and whereby the heteroaryl radicals or tautomeric forms thereof may be attached via any suitable atom.
  • Said heteroaryl ring(s) are optionally substituted, e.g. as indicated above for "aryl”.
  • arylalkyl refers to an alkyl group as defined above, substituted by an aryl group, as defined above.
  • arylalkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
  • aryl-lower alkyl refers to the above moiety but wherein the alkyl group is a "lower alkyl” group.
  • heteroarylalkyl refers to an alkyl group as defined above, substituted by a heteroaryl group, as defined above.
  • heteroaryl-lower alkyl refers to the above moiety but wherein the alkyl group is a "lower alkyl” group.
  • aryl-cycloalkyl refers to a cycloalkyl group as defined above, substituted or annelated by an aryl group, as defined above.
  • aryl-cycloalkyl moieties include, but are not limited to, phenylcyclopentyl, 2,3-dihydro-1 H- indenyl, 1,2,3,4-tetrahydronaphthalenyl and the like.
  • aryl-heterocycloalkyl refers to a heterocycloalkyl group as defined above, substituted or annelated by an aryl group, as defined above.
  • aryl-heterocycloalkyl moieties include, but are not limited to, indolinyl, 1,2,3,4-tetrahydroquinolinyl and the like.
  • heteroaryl-cycloalkyl refers to a cycloalkyl group as defined above, substituted or annelated by a heteroaryl group, as defined above.
  • heteroaryl-cycloalkyl moieties include, but are not limited to, 5,6,7,8-tetrahydro-quinolinyl and the like.
  • heteroaryl-heterocycloalkyl refers to a heterocycloalkyl group as defined above, substituted or annelated by a heteroaryl group, as defined above.
  • heteroaryl-heterocycloalkyl moieties include, but are not limited to, 4-(thiazol-2-yl)piperazinyl, 5,6,7,8-tetrahydro-1,6-naphthyridinyl and the like.
  • cycloalkyl-aryl “heterocycloalkyl-aryl”, “cycloalkyl-heteroaryl”, and “heterocycloalkyl-heteroaryl”, as used herein, are defined analogously to the terms “aryl-cycloalkyl”, “aryl-heterocycloalkyl”, “heteroaryl-cycloalkyl” and “heteroaryl-heterocycloalkyl”, as defined above, but connected in the opposite direction, e.g. instead of 4-(thiazol-2-yl)piperazinyl the term refers to 2-(piperazin-1-yl)thiazolyl and the like.
  • alkoxy and aryloxy taken alone or in combinations, refer to the groups of -O-alkyl and -O-aryl respectively, wherein an alkyl group or an aryl group is as defined above.
  • substituents independently selected from but not limited to, e.g., amino (-NH 2 ), dimethylamino, nitro (-NO 2 ), halogen (F, Cl, Br, I), CF 3 , cyano (-CN), hydroxy, methoxy,
  • lower designates radicals and compounds having up to 6 carbon atoms.
  • lower alkyl designates saturated, straight-chain, or branched hydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n -butyl, s -butyl, isobutyl, t-butyl, and the like.
  • the peptidomimetics of the present invention can also be diastereomers (e.g. epimers) of the compounds of formula (I) based on chiral centers where the absolute stereochemistry is not explicitly defined in the above description.
  • These stereoisomers can be prepared by a modification of the process described below in which epimers or enantiomers of chiral starting materials are used. In case of ambiguous stereochemistry in the above description each single epimer is part of the present invention as well as a mixture of both.
  • a further embodiment of the present invention may also include compounds, which are identical to the compounds of formula (I), except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in 2 H (D), 3 H, 11 C, 14 C, 127 I etc.
  • isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in the therapy and/or diagnostic, for example, but not limited to, where a fine-tuning of in vivo half-life time could lead to an optimized dosage regimen.
  • a particular embodiment of the invention relates to derivatives of general formula (I), wherein specifically
  • D-isomers e.g. D Lys(Ar1) corresponds to the epimer at the 2-position of the appropriate amino acid described above.
  • the compounds of the general formula (I) are selected from the group consisting of:
  • the compounds of the general formula (I) are selected from the group consisting of:
  • a further embodiment of the invention relates to the preparation of the present ⁇ -hairpin peptidomimetics by a process which comprises the steps of
  • the process of the invention can advantageously be carried out as parallel array synthesis to yield libraries of template-fixed ⁇ -hairpin peptidomimetics of the above general formula (I).
  • Such parallel synthesis allow one to obtain arrays of numerous (normally 24 to 192, typically 96) compounds of general formula (I) in high yields and defined purities, minimizing the formation of dimeric and polymeric by-products.
  • the proper choice of the functionalized solid-support i.e. solid support plus linker molecule
  • template and site of cyclization play thereby key roles.
  • the functionalized solid support is conveniently derived from polystyrene crosslinked with, preferably 1-5%, divinylbenzene; polystyrene coated with polyethyleneglycol spacers (Tentagel ® ); and polyacrylamide resins (see also Obrecht, D.; Villalgordo, J.-M, "Solid- Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries", Tetrahedron Organic Chemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998 ).
  • the solid support is functionalized by means of a linker, i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures.
  • a linker i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures.
  • linker i.e. a bifunctional spacer molecule which contains on one end an anchoring group for attachment to the solid support and on the other end a selectively cleavable functional group used for the subsequent chemical transformations and cleavage procedures.
  • reaction vessels normally 24 to 192, typically 96
  • 25 to 1000 mg preferably 100 mg
  • the appropriate functionalized solid support which is preferably derived from polystyrene cross-linked with 1 to 3% of divinylbenzene, or from Tentagel resin.
  • the solvent to be used must be capable of swelling the resin and includes, but is not limited to, dichloromethane (DCM), dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene, tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE), isopropylalcohol and the like.
  • Solvent mixtures containing as at least one component a polar solvent e. g. 20% TFE/DCM, 35% THF/NMP
  • Suitable protecting groups for amino acids and, respectively, for their residues are, for example, - for the amino group (as is present e.g. also in the side-chain of lysine)
  • the 9-fluorenylmethoxycarbonyl- (Fmoc)-protected amino acid derivatives are preferably used as the building blocks for the construction of the template-fixed ⁇ -hairpin loop mimetics of formula (I).
  • the deprotection i. e. cleaving off of the Fmoc group, 20% piperidine in DMF or 2% DBU/2% piperidine in DMF can be used.
  • the quantity of the reactant i. e. of the amino acid derivative, is usually 1 to 20 equivalents based on the milliequivalents per gram (meq/g) loading of the functionalized solid support (typically 0.1 to 2.85 meq/g for polystyrene resins) originally weighed into the reaction tube. Additional equivalents of reactants can be used, if required, to drive the reaction to completion in a reasonable time.
  • the reaction tubes, in combination with the holder block and the manifold, are reinserted into the reservoir block and the apparatus is fastened together. Gas flow through the manifold is initiated to provide a controlled environment, for example, nitrogen, argon, air and the like. The gas flow may also be heated or chilled prior to flow through the manifold.
  • Heating or cooling of the reaction wells is achieved by heating the reaction block or cooling it externally with isopropanol/dry ice and the like to bring about the desired synthetic reactions. Agitation is achieved by shaking or magnetic stirring (within the reaction tube).
  • the preferred workstations are Labsource's Combi-chem station and MultiSyn Tech's-Syro synthesizer.
  • Amide bond formation requires the activation of the ⁇ -carboxyl group for the acylation step. If this activation is being carried out by means of the commonly used carbodiimides, such as dicyclohexylcarbodiimide (DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068 ) or diisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res. Commun.1976, 73, 336-342 ), the resulting dicyclohexylurea and diisopropylurea is insoluble and, respectively, soluble in the solvents generally used.
  • DCC dicyclohexylcarbodiimide
  • DIC Diisopropylcarbodiimide
  • 1-hydroxybenzotriazole In a variation of the carbodiimide method 1-hydroxybenzotriazole (HOBt, König & Geiger, Chem. Ber 1970, 103, 788-798 ) is included as an additive to the coupling mixture. HOBt prevents dehydration, suppresses racemization of the activated amino acids and acts as a catalyst to improve the sluggish coupling reactions.
  • Certain phosphonium reagents have been used as direct coupling reagents, such as benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP, Castro et al., Tetrahedron Lett.
  • these phosphonium and uronium reagents are also suitable for in situ formation of HOBt esters with the protected amino acid derivatives. More recently diphenoxyphosphoryl azide (DPPA) or O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TATU) or O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt, Carpino et al., Tetrahedron Lett. 1994, 35, 2279-2281 ) have also been used as coupling reagents.
  • DPPA diphenoxyphosphoryl azide
  • TATU O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium te
  • the resin-bound intermediate within each reaction tube is washed free of excess of retained reagents, of solvents, and of by-products by repetitive exposure to pure solvent(s).
  • Washing procedures are repeated up to about 30 times (preferably about 5 times), monitoring the efficiency of reagent, solvent, and by-product removal by methods such as TLC, GC, LC-MS or inspection of the washings.
  • the solvent is removed by evaporation, the fully protected cyclic peptide derivative is dissolved in a solvent which is not miscible with water, such as DCM, and the solution is extracted with water or a mixture of water-miscible solvents, in order to remove any excess of the coupling reagent.
  • a solvent which is not miscible with water such as DCM
  • the fully protected peptide derivative is treated with 95% TFA, 2.5% H 2 O, 2.5% TIS or another combination of scavengers for effecting the cleavage of protecting groups.
  • the cleavage reaction time is commonly 30 minutes to 12 hours, preferably about 2.5 hours.
  • the volatiles are evaporated to dryness and the crude peptide is dissolved in 20% AcOH in water and extracted with isopropyl ether or other solvents which are suitable therefor.
  • the aqueous layer is collected and evaporated to dryness, and the fully deprotected cyclic peptide derivative of formula (I) is obtained as end-product.
  • this peptide derivative can be used directly for biological assays, or it has to be further purified, for example by preparative HPLC.
  • the building blocks for the peptidomimetics of the present invention can be synthesized according to the literature methods (examples described below) or are known to a person skilled in the art and/or are commercially available. A few additional new syntheses were carried out for this invention and are described in the examples. All other corresponding amino acids have been described either as unprotected or as Boc- or Fmoc-protected racemates, (D)- or (L)-isomers. It will be appreciated that unprotected amino acid building blocks can be easily transformed into the corresponding Fmoc-protected amino acid building blocks required for the present invention by standard protecting group manipulations. Reviews describing general methods for the synthesis of ⁇ -amino acids include: R.
  • Hydrolytic enzymes involve hydrolysis of amides and nitriles by aminopeptidases or nitrilases, cleavage of N-acyl groups by acylases, and ester hydrolysis by lipases or proteases. It is well documented that certain enzymes will lead specifically to pure (L)-enantiomers whereas others yield the corresponding (D)-enantiomers (e.g.: R. Duthaler, Tetrahedron Report 1994, 349, 1540-1650 ; R. M. Williams, "Synthesis of optically active ⁇ -amino acids", Tetrahedron Organic Chemistry Series, Vol.7, J. E. Baldwin, P. D. Magnus (Eds.), Pergamon Press., Oxford 1989 ).
  • the ⁇ -hairpin peptidomimetics of this invention can be used in a wide range of applications in order to selectively modulate the activity of the CXCR7 receptor and are thus useful in the treatment of a variety of diseases and disorders mediated by or sustained through the activity of CXCR7 or in the support of therapeutic treatments of specific disease conditions of primarily different cause, for example but not limited to the areas of dermatological disorders, metabolic diseases, inflammatory diseases, fibrotic diseases, infectious diseases, neurological diseases, cardiovascular diseases, respiratory diseases, gastro-intestinal tract disorders, urological diseases, ophthalmic diseases, stomatological diseases, haematological diseases and cancer, or the mobilisation of stem cells, in man or, due to their similar etiology, in other mammals.
  • diseases or conditions such as, but not limited to, HIV infections, Epstein-Barr Virus infection; diabetes mellitus (Type I and/or Type II); conjunctivitis, scleritis, uveitis, rhinosinusitis, Whim syndrome, lupus erythematosus, osteoarthritis, rheumatoid arthritis, synovitis, psoriasis, multiple sclerosis, Crohns disease, inflammatory bowel disease, mixed connective tissue disease, chronic lymphocytic thyroiditis, Graves' disease, graftversus-host disease, Sjögren's syndrome; dry eye syndrome, glaucoma, age-related macular degeneration; pulmonary arterial hypertension, pulmonary hypoxia, atherosclerosis, myocarditis, heart failure, such as myocardial infarction, arterial thrombosis, stroke, angiogenesis; chronic obstructive pulmonary disease, id
  • the ⁇ -hairpin peptidomimetics can be administered singly, as mixtures of several ⁇ -hairpin peptidomimetics or in combination with other pharmaceutically active agents.
  • the ⁇ -hairpin peptidomimetics may be administered per se or applied as a pharmaceutical preparation, e.g. an appropriate formulation together with carriers, diluents or excipients well known in the art.
  • compositions comprising ⁇ -hairpin peptidomimetics of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the active ⁇ -hairpin peptidomimetics into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.
  • ⁇ -hairpin peptidomimetics of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art.
  • Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.
  • the ⁇ -hairpin peptidomimetics of the invention may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline solution.
  • the solution may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the ⁇ -hairpin peptidomimetics of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.
  • the compounds can be readily formulated by combining the active ⁇ -hairpin peptidomimetics of the invention with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the ⁇ -hairpin peptidomimetics of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion of a patient to be treated.
  • suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents.
  • desintegrating agents may be added, such as cross-linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • solid dosage forms may be sugar-coated or enteric-coated using standard techniques.
  • suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc.
  • flavoring agents, preservatives, coloring agents and the like may be added.
  • the composition may take the form of tablets, lozenges, etc. formulated as usual.
  • the ⁇ -hairpin peptidomimetics of the invention are conveniently delivered in form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide or another suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide or another suitable gas.
  • the dose unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the ⁇ -hairpin peptidomimetics of the invention and a suitable powder base such as lactose or starch.
  • the compounds may also be formulated in rectal or vaginal compositions such as solutions for enema or suppositories together with appropriate suppository bases such as cocoa butter or other glycerides.
  • the ⁇ -hairpin peptidomimetics of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection.
  • the ⁇ -hairpin peptidomimetics of the invention may be formulated with suitable polymeric or hydrophobic-materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts.
  • ⁇ -hairpin peptidomimetics of the invention may be delivered using a sustained-release system, such as semipermeable matrices of solid polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 3 years. Depending on the chemical nature and the biological stability of the therapeutic agent, additional strategies for protein stabilization may be employed.
  • ⁇ -hairpin peptidomimetics of the invention may contain charged residues, they may be included in any of the above-described formulations as such or as pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than are the corresponding free base forms.
  • the compounds of the present invention and their pharmaceutical acceptable salts may be used per se or in any appropriate formulation in morphological different solid state forms, which may or may not contain different amounts of solvent, e.g. hydrate remaining from the crystallization process.
  • ⁇ -hairpin peptidomimetics of the invention will generally be used in an amount effective to achieve the intended purpose. It is to be understood that the amount used will depend on a particular application.
  • the ⁇ -hairpin peptidomimetics of the invention or compositions thereof are administered or applied in a therapeutically effective amount. Determination of a therapeutically effective amount is well within the capacities of those skilled in the art, especially in view of the detailed disclosure provided herein.
  • the effective dosage of the active ingredients employed may vary depending on the particular compound or pharmaceutical preparation employed, the mode of administration and the severity and type of the condition treated.
  • the dosage regimen is selected in accordance with factors including the route of administration and the clearance pathway, e.g. the renal and hepatic function of the patient.
  • a physician, clinician or veterinarian skilled in the art can readily determine and prescribe the amount of the single active ingredients required to prevent, ameliorate or arrest the progress of the condition or disease.
  • Optimal precision in achieving concentration of active ingredients without toxicity requires a regimen based on the kinetics of the active ingredients' availability to the target sites. This involves a consideration of the distribution, equilibrium, and elimination of the active ingredients.
  • the effective local concentration of the ⁇ -hairpin peptidomimetics of the invention may not be related to plasma concentration.
  • One having the skills in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
  • Method A and Method B Two general methods, Method A and Method B, for the synthesis of the peptide-mimetics of the present invention are exemplified here. This is to demonstrate the concept in principle and does not limit or restrict the present invention in any way. A person skilled in the art is easily able to modify these procedures, especially, but not limited to, choosing a different starting position within the ring system, to still achieve the preparation of the claimed cyclic peptidomimetic compounds of the present invention.
  • 2-chlorotritylchloride resin ( Barlos et al. Tetrahedron Lett. 1989, 30, 3943-3946 ) (100-200 mesh, polystyrene, 1% DBV crosslinked, 1.4 mmol/g loading, 0.7 mmol) was filled into a dried flask.
  • the resin was suspended in CH 2 Cl 2 (2.5 ml) and allowed to swell at room temperature for 30 min.
  • the resin was treated with 0.43 mmol (0.6 eq) of the first suitably protected amino acid residue and 488 ⁇ l (4eq) of diisopropylethylamine (DIPEA) in CH 2 Cl 2 (2.5 ml), the mixture was shaken at 25°C for 4 hours.
  • DIPEA diisopropylethylamine
  • the resin was washed with CH 2 Cl 2 (1x), DMF (1x), CH 2 Cl 2 (1x), DMF(1x), CH 2 Cl 2 (2x).
  • the resin was shaken in 30 ml CH 2 Cl 2 /MeOH/DIPEA (17:2:1) for 30 min; then washed in the following order with CH 2 Cl 2 (1x), DMF (1x), CH 2 Cl 2 (1x), MeOH (1x), CH 2 Cl 2 (1x), MeOH (1x), CH 2 Cl 2 (2x), Et 2 O (2x) and dried under vacuum for 6 hours.
  • 2-chlorotritylchloride resin (100-200 mesh, polystyrene, 1% DBV crosslinked, 1.4 mmol/g loading) is swollen in dry CH 2 Cl 2 for 30 min (7 ml CH 2 Cl 2 per g resin).
  • a solution of 0.8 eq of suitably side-chain protected Fmoc-AA-OH and 6 eq of DIPEA in dry CH 2 Cl 2 /DMF (4:1) (10 ml per g resin) is added. After shaking for 2-4 h at rt the resin is filtered and washed successively with CH 2 Cl 2 , DMF, CH 2 Cl 2 , DMF and CH 2 Cl 2 .
  • the following preloaded resins were prepared: Fmoc-Ile-2-chlorotrityl resin, Fmoc-Arg-2-chlorotrityl resin, Fmoc-Trp-2-chlorotrityl resin, Fmoc-Thr-2-chlorotrityl resin, Fmoc- D Pro-2-chlorotrityl resin, Fmoc-Ser-2-chlorotrityl resin, Fmoc-Agp-2-chlorotrityl resin, Fmoc-Agb-2-chlorotrityl resin, Fmoc-Tic-2-chlorotrityl resin, Fmoc-Tiq-2-chlorotrityl resin, Fmoc-Oic-2-chlorotrityl resin, Fmoc-(4 S )-Hyp(Bn)-2-chlorotrityl resin, Fmoc-Pro((4S)NHBz)-2
  • Steps 3 to 6 are repeated to add each amino acid residue.
  • Step Reagent Time 1 CH 2 Cl 2 , wash and swell (manual) 1 x 3 min 2 DMF, wash and swell 1 x 60 min 3 40 % piperidine/DMF 1 x 5 min and 1 x 15 min 4 DMF, wash 5 x 1 min 5 5 equiv. Fmoc amino acid/DMF + 5 eq. HCTU + 10 eq. DIPEA 2 x 60 min 6 DMF, wash 5 x 1 min 7 CH 2 Cl 2 , wash (at the end of the synthesis) 3 x 1 min
  • Steps 3 to 6 are repeated to add each amino acid residue.
  • Step Reagent Time 1 CH 2 Cl 2 , wash and swell (manual) 1 x 3 min 2 DMF, wash and swell 1 x 60 min 3 40 % piperidine/DMF 1 x 5 min and 1 x 15 min 4 DMF, wash 5 x 1 min 5 3.5 equiv. Fmoc amino acid/DMF + 3.5 eq. HCTU + 7 eq. DIPEA 2 x 60 min 6 DMF, wash 5 x 1 min 7 CH 2 Cl 2 , wash (at the end of the synthesis) 3 x 1 min
  • the resin was suspended in 1 ml of 1% TFA in CH 2 Cl 2 ( v / v ; 0.14 mmol) for 3 minutes and filtered, and the filtrate was neutralized with 1 ml of 20% DIPEA in CH 2 Cl 2 ( v / v; 1.15 mmol). This procedure was repeated four times to ensure completion of the cleavage. The resin was washed three times with 1 ml of CH 2 Cl 2 . The CH 2 Cl 2 layers containing product were evaporated to dryness.
  • the fully protected linear peptide was solubilised in 8 ml of dry DMF. Then 2 eq. of HATU in dry DMF (1-2 ml) and 4 eq. of DIPEA in dry DMF (1-2 ml) were added to the peptide, followed by stirring for 16 h. The volatiles were removed by evaporation. The crude cyclic peptide was dissolved in 7 ml of CH 2 Cl 2 and extracted three times with 4.5 ml 10% acetonitrile in water ( v / v ). The CH 2 Cl 2 layers were evaporated to dryness.
  • Examples 1 - 5 are shown in Table 1.
  • the peptides were synthesized according general Method B starting with the amino acid L-isoleucin, which was grafted to the resin (Fmoc-Ile-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Ile-Thr- D Pro-P 4 -P 3 -P 2 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • the peptides were synthesized according general Method B starting with the amino acid L-arginin, which was grafted to the resin (Fmoc-Arg-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Arg-P 2 -P 1 -T 2 -T 1 -P 4 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Example 8 and 9 are shown in Table 1.
  • the peptides were synthesized according general Method B starting with the amino acid L-tryptophan, which was grafted to the resin (Fmoc-Trp-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Trp-Arg- D Arg-Ile-T 2 -T 1 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Example 10-16 are shown in Table 1.
  • the peptides were synthesized according general Method B starting with the amino acid L-threonin, which was grafted to the resin (Fmoc-Thr-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Thr-T 1 -P 4 -P 3 -P 2 -P 1 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Examples 17 - 20 are shown in Table 1.
  • the peptides were synthesized according general Method A starting with the amino acid D-proline, which was grafted to the resin (Fmoc- D Pro-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin- D Pro-P 4 -P 3 -P 2 -P 1 -T 1 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • the peptides were synthesized according general Method B starting with the amino acid D-proline, which was grafted to the resin (Fmoc- D Pro-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin- D Pro-P 4 -P 3 -P 2 -P 1 -T 1 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Example 22 is shown in Table 1.
  • the peptide was synthesized according general Method B starting with the amino acid L-serin, which was grafted to the resin (Fmoc-Ser-2-chlorotrityl resin).
  • the linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin-Ser- D Pro-Trp-Arg- D Arg-Ile.
  • the product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Example 23 is shown in Table 1.
  • the peptide was synthesized according general Method B starting with the amino acid ( S )-2-amino-3-guanidinopropanoic acid, which was grafted to the resin (Fmoc-Agp-2-chlorotrityl resin).
  • the linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin-Agp- D Arg-Ile-Thr- D Pro-Trp.
  • the product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Example 24 is shown in Table 1.
  • the peptide was synthesized according general Method B starting with the amino acid ( S )-2-amino-4-guanidinobutanoic acid, which was grafted to the resin (Fmoc-Agb-2-chlorotrityl resin).
  • the linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin-Agb- D Arg-Ile-Thr- D Pro-Trp.
  • the product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Examples 25 - 40, 74, 75 and 78 are shown in Table 1.
  • the peptides were synthesized according general Method B starting with the amino acid (3 S )-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid, which was grafted to the resin (Fmoc-Tic-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Tic-T 1 -P 4 -P 3 -P 2 -P 1 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • the peptides were synthesized according general Method B starting with the amino acid (2 S ,3a S ,7a S )-octahydro-1H-indole-2-carboxylic acid, which was grafted to the resin (Fmoc-Oic-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Oic- D Pro((4 R )NH 2 )-Arg-Trp- D Phe-P 1 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above. After lyophilisation, the products were obtained as white powders and characterised by HPLC-MS, analytical method C as described above. For analytical data, see Ex. 41, 42 in Table 1.
  • Examples 43 - 46 are shown in Table 1.
  • the peptides were synthesized according general Method B starting with the amino acid L-tryptophan, which was grafted to the resin (Fmoc-Trp-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Trp- D Phe-Trp-T 2 -T 1 -P 4 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as describes above.
  • Example 47 is shown in Table 1.
  • the peptide was synthesized according general Method B starting with the amino acid L-tryptophan, which was grafted to the resin (Fmoc-Trp-2-chlorotrityl resin).
  • the linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin-Trp-Arg- D Arg-Ile-Mor- D Pro.
  • the product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Examples 48 - 50 are shown in Table 1.
  • the peptides were synthesized according general Method B starting with the amino acid (2 S ,4 S )-4-(benzyloxy)pyrrolidine-2-carboxylic acid, which was grafted to the resin (Fmoc-(4 S )-Hyp(Bn)-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-(4 S )-Hyp(Bn)-T 1 -P 4 -P 3 -P 2 -P 1 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above. After lyophilisation, the products were obtained as white to off-white powders and characterised by HPLC-MS, analytical method C as described above. For analytical data, see Ex. 48, 49, 50 in Table 1.
  • Example 51 is shown in Table 1.
  • the peptide was synthesized according general Method A starting with the amino acid (2 S ,4 S )-4-benzamidopyrrolidine-2-carboxylic acid, which was grafted to the resin (Fmoc-Pro((4 S )NHBz)-2-chlorotrityl resin).
  • the linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin-Pro((4 S )NHBz)- D Pro-Trp-His- D Tpr-His.
  • the product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Example 54 is shown in Table 1.
  • the peptide was synthesized according general Method B starting with the amino acid ( R )-piperidine-2-carboxylic acid, which was grafted to the resin (Fmoc- D Pip-2-chlorotrityl resin).
  • the linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin- D Pip-Trp-Arg- D Arg-Ile-Pro((3 S )OH).
  • the product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Example 55 is shown in Table 1.
  • the peptide was synthesized according general Method B starting with the amino acid (2 R ,3 S )-3-hydroxypyrrolidine-2-carboxylic acid, which was grafted to the resin (Fmoc- D Pro((3 S )OH-2-chlorotrityl resin).
  • the linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin- D Pro((3S)OH-Trp-Arg- D Arg-Ile-Thr).
  • the product was cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • the peptides were synthesized according general Method B starting with the amino acid L-threonin, which was grafted to the resin (Fmoc-Thr-2-chlorotrityl resin).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-Thr-T 1 -P 4 -P 3 -P 2 -P 1 .
  • the products were cleaved from the resin, cyclized, deprotected and purified by preparative reverse phase LC-MS as described above.
  • Examples 71, 73, 77, 79 and 80 are shown in Table 1.
  • the peptides were synthesized according general Method B starting with the appropriate protected amino acid at the position T 2 or in case of Ex. 73 at the position T 1 according Table 1 , which was grafted to the resin (Fmoc-T 2 -chlorotrityl resin respectively Fmoc-T 1 -chlorotrityl).
  • the linear peptides were synthesized on the solid support according to the procedure described above in the following sequence: Resin-T 2 -T 1 -P 3 -P 2 -P 2 -P 1 respectively Resin-T 1 -P 4 -P 3 -P 2 -P 1 -T 2 .
  • Fmoc-protected ( S )-2-amino-5-(pyrimidin-2-yl-amino)pentanoic acid was used as starting material.
  • the products were cleaved from the resin and cyclized.
  • Deprotection according the above standard procedure using TFA/TIS/H 2 O resulted in a reduction to the desired molecule containing the Orn(A56) residue. Consequently the compounds were purified by preparative reverse phase LC-MS as described above.
  • Example 68 is shown in Table 1.
  • the peptide was synthesized according general Method B starting with the amino acid L-threonin, which was grafted to the resin (Fmoc-Thr-2-chlorotrityl resin).
  • the linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin-Thr- D Pro-Trp-Orn(Ar2)- D Arg-Ile.
  • the product was cleaved from the resin and cyclized. In deviation from above general procedure, deprotection was done (avoiding TIS) with a mixture of TFA/H 2 O (95:5) and monitored for completion.
  • the compound was purified by preparative reverse phase LC-MS as described above.
  • Example 76 is shown in Table 1.
  • the peptide was synthesized according general Method B starting with the amino acid (3 S )-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid, which was grafted to the resin (Fmoc-Tic-2-chlorotrityl resin).
  • the linear peptide was synthesized on the solid support according to the procedure described above in the following sequence: Resin-Tic- D Pro((4 R )NH 2 )-Arg-Trp- D Phe-Orn(Ar2).
  • the product was cleaved from the resin and cyclized. In deviation from above general procedure, deprotection was done (avoiding TIS) with a mixture of TFA/H 2 O (95:5) and monitored for completion.
  • the compound was purified by preparative reverse phase LC-MS as described above.
  • Lyophilized peptides were weighed on a Microbalance (Mettler MX5) and dissolved in DMSO to a final concentration of 10 mM unless otherwise stated. Stock solutions were kept at +4°C, and protected from light.
  • the PathHunter CHO-CXCR7 (DiscoverX) assay was performed according to the manufacturer's protocol. In brief, CHO CXCR7 ⁇ -arrestin cells were seeded at a density of 5000 cells per well in 40 ⁇ l of F12 medium in black 96-half volume well culture plates and incubated overnight at 37°C in a humidified atmosphere with 5% CO 2 . The next day, serial dilutions of PEM compounds have been prepared in DMSO and subsequently diluted in HBSS buffer containing 0.1% BSA.

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Claims (16)

  1. Composés de formule générale (I)
    Figure imgb0085
    dans lequel les éléments T et P sont connectés dans l'une et l'autre direction depuis le point d'attache carbonyle (C=O) à l'azote (N) de l'élément suivant et dans lequel :
    - soit
    T1 est un résidu acide α aminé selon l'une des formules
    Figure imgb0086
    Figure imgb0087
    Figure imgb0088
     et
    T2 est un résidu acide α aminé selon l'une des formules
    Figure imgb0089
    Figure imgb0090
    - soit
    T1 est un résidu acide α aminé selon l'une des formules
    Figure imgb0091
    Figure imgb0092
     et
    T2 est un résidu acide α aminé selon l'une des formules AA11 à AA17 ci-dessus, ou un résidu acide α aminé selon l'une des formules
    Figure imgb0093
    Figure imgb0094
    Figure imgb0095
    P1, P3 et P4 sont indépendamment -NR1CH(R29)CO-; -NR1CH(R30)CO-; ou -NR1CH(R31)CO-;
    P2 est un résidu acide α aminé selon l'une des formules
    Figure imgb0096
    A est O; NR17; S; SO; ou SO2;
    X est OH; NH2; OR16; NR1R16; ou NR17R16;
    Y est NH2; F; OR16; NR1R16; ou NR17R16;
    R1, R2 et R3 sont indépendamment H; CF3; alkyle inférieur; alcényle inférieur; aryl-alkyle inférieur; ou hétéroaryl-alkyle inférieur;
    R4, R5, R6, R7 et R8 sont indépendamment H; F; CF3; alkyle inférieur; alcényle inférieur; cycloalkyle; hétérocycloalkyle; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; -(CHR15)oOR17; -(CHR15)oSR17; -(CHR15)oNR17R18; -(CHR15)oOCOR17R18; -(CHR15)oNR1CONR17R18; -(CHR15)oNR1COR17; -(CHR15)oCOOR17; -(CHR15)oCONR17R18; -(CHR15)oPO(OR1)2; -(CHR15)oSO2R17; -(CHR15)oNR1SO2R17; -(CHR15)oSO2NR17R18; -(CR1R15)oR35; ou -(CHR1)nO(CHR2)mR35; ou
    R4 et R2 pris ensemble peuvent former : =O; -(CHR15)p; -(CH2)nO(CH2)m-; -(CH2)nS(CH2)m-; ou -(CH2)nNR1(CH2)m-; ou R4 et R5; R5 et R6; R6 et R7; R7 et R8; ou R6 et R9 pris ensemble peuvent former : -(CHR15)p-; -(CH2)nO(CH2)m-; -(CH2)nS(CH2)m-; ou -(CH2)nNR1(CH2)m-; ou
    R4 et R5 sont indépendamment X;
    R9, R10, R11 et R12 sont indépendamment H; F; CF3; alkyle inférieur; alcényle inférieur; cycloalkyle; hétérocycloalkyle; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; -(CHR15)rOR17; -(CHR15)rSR17; -(CHR15)rNR17R18; -(CHR15)rOCONR17R18; -(CHR15)rNR1CONR17R18; -(CHR15)rR1NCOR17; -(CHR15)oCOOR17; -(CHR15)oCONR17R18; -(CHR15)rPO(OR1)2; -(CHR15)rSO2R17; -(CHR15)rNR1SO2R17; -(CHR15)rSO2NR17R18; -(CR1R15)oR35; ou -(CHR1)rO(CHR2)oR35; ou
    R11 et R12 pris ensemble peuvent former : =O; ou =NR1;
    R13 et R14 sont indépendamment H; F; Cl; Br; CF3; OCF3; OCHF2; CN; NO2; alkyle inférieur; alcényle inférieur; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; -(CHR15)oOR17; -(CHR15)oSR17; -(CHR15)oNR17R18; -(CHR15)oOCONR17R18; -(CHR15)oNR1CONR17R18; -(CHR15)oR1NCOR17; -(CHR15)oCOOR17; -(CHR15)oCONR17R18; -(CHR15)oPO(OR1)2; -(CHR15)oSO2R17; -(CHR15)oNR1SO2R17; -(CHR15)oSO2NR17 R18; -(CR1R15)oR35; ou -(CHR1)rO(CHR2)oR35;
    R15 est H; F; CF3; alkyle inférieur; alcényle inférieur; cycloalkyle; hétérocycloalkyle; cycloalkyl-alkyle inférieur; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; -(CHR1)oOR17; -(CHR1)oSR17;
    -(CHR1)oNR17R18; -(CHR1)oNR20C(=NR19)NR17R18; -(CHR1)oCOOR17; -(CHR1)oNR1CONR17R18; -(CHR1)oSO2R17; ou -(CHR1)oNSO2R17R18;
    R16 est CF3; alkyle inférieur; alcényle inférieur; cycloalkyle; hétérocycloalkyle; cycloalkyl-alkyle inférieur; hétérocycloalkyl-alkyle inférieur; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; cycloalkyl-aryle;
    hétérocycloalkyl-aryle; cycloalkyl-hétéroaryle; hétérocycloalkyl-hétéroaryle; aryl-cycloalkyle; aryl-hétérocycloalkyle; hétéroaryl-cycloalkyle hétéroaryl-hétérocycloalkyle; -(CHR1)sOR17; -(CHR1)sSR17;
    -(CHR1)sNR17R18; -(CHR1)oCOR17; -(CHR1)oCOOR17; -(CHR1)oCONR17R18; ou -(CHR1)oSO2R17;
    R17, R18, R19 et R20 sont indépendamment H; alkyle inférieur; alcényle inférieur; alcoxy inférieur; cycloalkyle; hétérocycloalkyle; cycloalkyl-alkyle inférieur; hétérocycloalkyl-alkyle inférieur; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; cycloalkyl-aryle;
    hétérocycloalkyl-aryle; cycloalkyl-hétéroaryle; hétérocycloalkyl-hétéroaryle; aryl-cycloalkyle; aryl-hétérocycloalkyle; hétéroaryl-cycloalkyle; ou hétéroaryl-hétérocycloalkyle ; ou
    les éléments structurels -NR17R18 et -NR19R20 peuvent former indépendamment : hétérocycloalkyle; aryl-hétérocycloalkyle; ou hétéroaryl-hétérocycloalkyle; ou un groupe selon l'une des formules
    Figure imgb0097
    Figure imgb0098
    Z, Z' et Z" sont indépendamment -CR39; ou N;
    R21, R22, R23 et R24 sont indépendamment H; F; CF3; alkyle inférieur; alcényle inférieur; hétérocycloalkyle; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; -(CHR1)oOR17; -(CHR1)oSR17; -(CHR1)oNR2R17; -(CHR1)oOCONR2R17; -(CHR1)oNR2CONR3R17; -(CHR1)oNR2COR17; -(CHR1)oCOOR17; -(CHR1)oCONR2R17; -(CHR1)oPO(OR2)2; -(CHR1)oSO2R17; -(CHR1)oNR2SO2R17; -(CHR1)oSO2NR2R17; -(CR1R2)oR38 ou -(CHR1)nO(CHR2)mR38;
    R25 et R26 sont indépendamment H; F; CF3; alkyle inférieur; alcényle inférieur; cycloalkyle; hétérocycloalkyle; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; -(CHR1)rOR17; -(CHR1)rSR17; -(CHR1)rNR2R17; -(CHR1)rOCONR2R17; -(CHR1)rNR2CONR3R17; -(CHR1)rNR2COR17; -(CHR1)oCOOR17; -(CHR1)oCONR2R17; -(CHR1)rPO(OR2)2; -(CHR1)rSO2R17; -(CHR1)rNR2SO2R17; -(CHR1)rSO2NR2R17; -(CR1R2)oR38; ou -(CHR1)rO(CHR2)oR38;
    R27 est H; F; Cl; Br; CF3; OCF3; OCHF2; CN; NO2; alkyle inférieur; alcényle inférieur; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; -(CHR1)oOR17; -(CHR1)oSR17; -(CHR1)oNR2R17; -(CHR1)oOCONR2R17; -(CHR1)oNR2CONR3R17; -(CHR1)oNR2COR17; -(CHR1)oCOOR17; -(CHR1)oCONR2R17; -(CHR1)oPO(OR2)2; -(CHR1)oSO2R17; -(CHR1)oNR2SO2R17; -(CHR1)oSO2NR2R17; -(CR1R2)oR38; ou -(CHR1)rO(CHR2)oR38;
    R29 est H; alkyle; alcényle; cycloalkyl-alkyle inférieur; hétérocycloalkyl-alkyle inférieur; -(CHR4)oOR17; -(CHR4)oSR17; ou -(CHR4)rNR17R18;
    R30 est -(CR1R4)nOR35; -(CH2)nO(CH2)mR35; -(CH2)nS(CH2)mR35; ou -(CH2)nNR1(CH2)mR35;
    R31 est alkyle; alcényle; -(CR1R15)qNR17R18; -(CR1R15)qNR2R16; -(CR1R15)qNR17R32; -(CR1R15)qNR17COR18; -(CH2)qC(=NR15)NR17R18; -(CH2)qC(=NOR19)NR17R18; -(CH2)qC(=NNR17N18)NR19R20; -(CR1R15)qNR20C(=NR19)NR17R18; -(CR1R15)qN=C(NR17R18)NR19R20; -(CR1R15)qOR17; -(CR1R15)qOR32; -(CR1R15)qSR17; -(CR1R15)qSO2R17; -(CR1R15)qNR17SO2R18; -(CR1R15)qSO2NR2R16; -(CR1R15)qSO2NR17R18; -(CR1R15)qSO2NR17R18;-(CR1R15)qNR19SO2NR17R18;-(CR1R15)qPO(OR2)2; -(CH2)nO(CH2)mNR17R18;-(CH2)nO(CH2)mC(=NR19)NR17R18; -(CH2)nO(CH2)mC(=NOR19)NR17R18; -(CH2)nO(CH2)mC(=NNR17R18)NR19R20; -(CH2)nO(CH2)mNR20C(=NR19)NR19R18; -(CH2)nO(CH2)mN=C(NR17R18)NR19R20; -(CH2)nS(CH2)mNR17R18; -(CH2)nS(CH2)mC(=NR19)NR17R18; -(CH2)nS(CH2)mC(=NOR19)NR17R18; -(CH2)nS(CH2)mC(=NNR17R18)NR19R20; -(CH2)nS(CH2)mNR20C(=NR19)NR17R18; -(CH2)nS(CH2)mN=C(NR17R18)NR19R20; -(CR1R15)qCOOR17; -(CR1R15)qCONR17R18; ou -(CR1R15)qCOR33; R32 est -COR29; -COR30; -CO(CR1R15)oR17; -CO(CR1R15)oOR17; -CO(CR1R15)oNR17R18; -CO(CR1R15)oNR2R16; -CO(CR1R29)NR17R18; -CO(CR1R30)NR17R18; -CO(CR1R34)NR17R18; -CO(CHR1)oCONR17R18; -CO(CHR1)oCONR17SO2R18; -CO(CR1R15)oNR17SO2R18; -CONR1(CHR17)nNR2(CHR15)mR16; -CO(CHR17)nO(CHR15)mR16; -CONR1(CHR17)nO(CHR15)mR16; -SO2R29; -SO2R30; -SO2(CR1R15)oR17; ou -SO2(CR1R15)oNR17R18;
    R33 est -NR1C(R2)(R29)COOR17; -NR1C(R2)(R29)CONR17R18;
    -NR1C(R2)(R30)COOR17; -NR1C(R2)(R30)CONR17R18; -NR1C(R2)(R34)COOR17; ou -NR1C(R2)(R34)CONR17R18;
    R34 est -(CR1R15)qNR17R18; -(CH2)qC(=NR19)NR17R18;
    -(CH2)qC(=NOR19)NR17R18; -(CH2)qC(=NNR17R18)NR19R20; -(CR1R15)qNR2C(=NR19)NR17R18; -(CR1R15)qN=C(NR17R18)NR19R20; -(CR1R15)qNR2OR17; -(CR1R15)qSR17; -(CR1R15)qSO2R17; -(CR1R15)qNR17SO2R18; -(CR1R15)qSO2NR1R16; -(CR1R15)qSO2NR17R18; -(CR1R15)qNR2SO2NR17R18; -(CR1R15)qPO(OR1)2; -(CH2)nO(CH2)mNR17R18; -(CH2)nO(CH2)mC(=NR19)NR17R18; -(CH2)nO(CH2)mC(=NOR19)NR17R18; -(CH2)nO(CH2)mC(=NNR17R18)NR19R20; -(CH2)nO(CH2)mNR20C(=NR19)NR17R18; -(CH2)nO(CH2)mN=C(NR17R18)NR19R20; -(CH2)nS(CH2)mNR17R18; -(CH2)nS(CH2)mC(=NR19)NR17R18; -(CH2)nS(CH2)mC(=NOR19)NR17R18; -(CH2)nS(CH2)mC(=NNR17R18)NR19R20; -(CH2)nS(CH2)mNR20C(=NR19)NR17R18; -(CH2)nS(CH2)mN=C(NR17R18)NR19R20; -(CR1R15)qCOOR17; ou -(CR1R15)qCONR17R18;
    R35 est un groupe aryle selon l'une des formules
    Figure imgb0099
     ou un groupe hétéroaryle selon l'une des formules
    Figure imgb0100
    Figure imgb0101
    Figure imgb0102
    Figure imgb0103
    Figure imgb0104
    Figure imgb0105
    Figure imgb0106
    Figure imgb0107
    Figure imgb0108
    Figure imgb0109
    Figure imgb0110
    Figure imgb0111
    R36 et R37 sont indépendamment H; F; Cl; Br; CF3; OCF3; OCHF2; CN; NO2; alkyle inférieur; alcényle inférieur; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; -(CH2)oR38; -(CH2)oR17; -O(CH2)oR38; -(CH2)oSR17; -(CH2)oOCONR17R18; -(CH2)oNR1CONR17R18; -(CH2)oNR1COR17; -(CH2)oNR1COOR17; -(CH2)oCONR17R18; -(CH2)oPO(OR1)2; -(CH2)oSO2R16; ou -(CH2)oCOR17;
    R38 est un groupe aryle selon la formule
    Figure imgb0112
    R39, R40 et R41 sont indépendamment H; F; Cl; Br; OH; NH2; NO2; CN; CF3; OCHF2; OCF3; -NR1R17; -(CH2)oCOOR17; -(CH2)oCONR1R17; alkyle inférieur; alcényle inférieur; ou alcoxy inférieur;
    R42 est H; alkyle inférieur; ou aryl-alkyle inférieur;
    n et m sont indépendamment un entier entre 0 et 5 sous réserve que n+m ≤ 6;
    o est un entier entre 0 et 4; p est un entier entre 2 et 6; q est un entier entre 1 et 6;
    r est un entier entre 1 et 3; s est un entier entre 0 et 4;
    et leurs sels pharmaceutiquement acceptables.
  2. Composés selon la revendication 1, dans lesquels
    R16 est CF3; alkyle inférieur; alcényle inférieur; cycloalkyle; hétérocycloalkyle; cycloalkyl-alkyle inférieur; hétérocycloalkyl-alkyle inférieur; aryle; hétéroaryle; aryl-alkyle inférieur; hétéroaryl-alkyle inférieur; -(CHR1)sOR17; -(CHR1)sSR17; -(CHR1)sNR17R18; -(CHR1)oCOR17; -(CHR1)oCOOR17; -(CHR1)oCONR17R18; ou -(CHR1)oSO2R17;
    R17, R18, R19 et R20 sont indépendamment H; alkyle inférieur; alcényle inférieur; alcoxy inférieur; cycloalkyle; hétérocycloalkyle; cycloalkyl-alkyle inférieur; hétérocycloalkyl-alkyle inférieur; aryle; hétéroaryle; aryl-alkyle inférieur; ou hétéroaryl-alkyle inférieur ; ou
    les éléments structurels -NR17R18 et -NR19R20 peuvent former indépendamment : hétérocycloalkyle; aryl-hétérocycloalkyle; ou hétéroaryl-hétérocycloalkyle; ou un groupe selon l'une des formules C1 à C8 ci-dessus;
    R31 est alkyle, alcényle; -(CR1R15)qNR17R18; -(CR1R15)qNR2R16; -(CR1R15)qNR17COR18; -(CH2)qC(=NR15)NR17R18; -(CR1 R15)qNR20C(=N R19)N R1 7 R18; -(CR1R15)qOR17; -(CR1R15)qSR17; -(CR1R15)qSO2R17; -(CR1R15)qNR17SO2R18; -(CR1R15)qSO2NR2R16; -(CR1R15)qSO2NR17R18; -(CH2)nO(CH2)mNR17R18; -(CH2)nO(CH2)mNR20C(=NR19)NR17R18; -(CH2)nS(CH2)mNR17R18; -(CH2)nS(CH2)mNR20C(=NR19)NR17R18; -(CR1R15)qCONR17R18; ou -(CR1R15)qCOR33;
    s est un entier entre 2 et 4;
    et leurs sels pharmaceutiquement acceptables.
  3. Composés selon la revendication 1, dans lesquels
    T1 est DPro; DPip; DTic; DTiq; DOic; DAzt; DPro((3R)OH); DPro((3S)OH); DPro((3R)NH2); DPro((3S)NH2); DPro((4R)OH); DPro((4S)OH); DPro((4R)NH2); DPro((4S)NH2); DPro((4S)NHBz); ou DMor;
    T2 est Thr; alloThr; Ser; hSer; DPro((3R)OH); DPro((3S)OH); Hyp(Bn); (4S)-Hyp(Bn); Pro((3R)NH2); Pro((3S)NH2); Pro((4R)NH2); Pro((4S)NH2); Pro((4S)F); Pro((4S)NHBz); ou Mor; ou
    quand T1 est DPro((3R)OH); DPro((3S)OH); DPro((3R)NH2); DPro((3S)NH2); DPro((4R)NH2); DPro((4S)NH2); DPro((4S)NHBz); ou DMor
    alors T2 peut, en plus, être Pro; Pip; Tic; Tiq; Oic; ou Azt;
    P1, P3 et P4 sont indépendamment Ala; Arg; Asn; Asp; Cit; Cys; Glu; Gln; Gly; His; Ile; Leu; Lys; Met; Orn; Phe; Pro; Ser; Thr; Trp; Tyr;Val; Abu; Agb; Agp; Ala(tBu); Ala(cPr); Ala(2Furyl); Ala(3Furyl); Ala(Ppz); Ala(1Pyraz); Ala(2Quin); Ala(3Quin); Ala(4Quin); Ala(Tet); Azt; Bbta; Bip; Cha; Chg; Dab; Dab(Ac); Dab(Cpr); Dab(iPr); Dab(4Me2NPhSO2), Dab(MeOEtNCO); Dab(MePpzCO); Dab(MeSO2); Dab(morphCO); Dab(1Nal); Dab(2Nal); Dap; Dap(CONH2); Dap(MeOEt); Dap((MeOEt)2); Deg; Gly(tBu); hArg; hCha; hCys; hHis; hLys; hPhe; hSer; hSer(Me); hTrp; hTyr; His(Me); His(Bn); Hyp(Bn); (4S)-Hyp(Bn); Hyp(4BrBn); Hyp(3CNBn); Hyp(4CNBn); Hyp(CONHPh); Hyp(Ph); Lys(Ac); Lys(Bz); Lys(cPr); Lys(iPr); Lys(Me); Lys(Nic); Lys((5R)OH); Lys(40xa); Met(O2); 1Nal; 2Nal; Nle; Nle(60Bn); OctG; Oic; Orn(cPr); Orn(iPr); 2Pal; 3Pal; 4Pal; Phe(2Cl); Phe(3Cl); Phe(4Cl); Phe(3,4Cl2); Phe(2F); Phe(3F); Phe(4F); Phe(4CN); Phe(4CF3); Phe(4COOMe); Phg; Pip; Pro((4R)Bn); Pro((4S)F); Pro((4S)cHex); Pro(5,5Me2); Ser(Bn); Ser(Me); Thi; allothr, Thr(Bn); Thz; Thz(5,5Me2); Tic; Tic(70H); Trp(7Aza); Trp(5Br); Trp(6Br); Trp(6CF3); Trp(5Cl); Trp(6Cl); Trp(5,6Cl); Trp(50H); Tyr(Bn); Tyr(Me); Tyr(4MeOCOBn); Tyr(Ph); Tyr(40HPh); Tza; Gln(Alk1); Gln(Alk2); Gln(Alk3); Gln(Alk4); Gln(Alk5); Gln(Alk6); Gln(Alk7); Gln(Alk8); Gln(Alk9); Gln(Alk10); Gln(Alk11); Gln(Alk12); Gln(Alk13); Gln(Alk14); Gln(Alk15); Gln(Alk16); Gln(Alk17); Gln(Alk18); Gln(Alk19); Gln(Alk20); Gln(Alk21); Gln(Alk22); Gln(Alk23); Gln(Alk24); Gln(Alk25); Gln(Alk26); Gln(Alk27); Gln(Alk28); Gln(Alk29); Gln(Alk30); Gln(Alk33); Gln(Alk32); Gln(Alk33); Gln(Alk34); Glu(cN1); Glu(cN2); Glu(cN3); Glu(cN4); Glu(cN5); Glu(cN6); Glu(cN7); Glu(cN8); Glu(cN9); Glu(cN10); Glu(cN11); Glu(cN12); Glu(cN13); Glu(cN14); Glu(cN15); Glu(cN16); Glu(cN17); Lys(Ar1); Lys(Ar2); Lys(Ar3); Lys(Ar4); Lys(Ar5); Lys(Ar6); Lys(Ar7); Lys(Ar8); Lys(Ar9); Lys(Ar10); Lys(Ar11); Lys(Ar12); Orn(Ar1); Orn(Ar2); Orn(Ar3); Orn(Ar4); Orn(Ar5); Orn(Ar6); Orn(Ar7); Orn(Ar8); Orn(Ar9); Orn(Ar10); Orn(Ar11); Orn(Ar12); Dab(Ar1); Dab(Ar2); Dab(Ar3); Dab(Ar4); Dab(Ar5); Dab(Ar6); Dab(Ar7); Dab(Ar8); Dab(Ar9); Dab(Ar10); Dab(Ar11); Dab(Ar12); Dab(S1); Dab(S2); Dab(S3); Dab(S4); Dab(S5); Dab(S6); Dab(S7); Dab(S8); Dab(S9); Dab(S10); Dab(S11); Dab(S12); Dab(S13); Dab(S14); Dab(S15); Dab(S16); Dab(S17); Dab(S18); Dab(A1); Dab(A2); Dab(A3); Dab(A4); Dab(A5); Dab(A6); Dab(A7); Dab(A8); Dab(A9); Dab(A10); Dab(A11); Dab(A12); Dab(A13); Dab(A14); Dab(A15); Dab(A16); Dab(A17); Dab(A18); Dab(A19); Dab(A20); Dab(A21); Dab(A22); Dab(A23); Dab(A24); Dab(A25); Dab(A26); Dab(A27); Dab(A28); Dab(A29); Dab(A30); Dab(A31); Dab(A32); Dab(A33); Dab(A34); Dab(A35); Dab(A36); Dab(A37); Dab(A38); Dab(A39); Dab(A40); Dab(A41); Dab(A42); Dab(A43); Dab(A44); Dab(A45); Dab(A46); Dab(A47); Dab(A48); Dab(A49); Dab(A50); Dab(A51); Dab(A52); Dab(A53); Dab(A54); Dab(A55); Orn(A1); Orn(A2); Orn(A3); Orn(A4); Orn(A5); Orn(A6); Orn(A7); Orn(A8); Orn(A9); Orn(A10); Orn(A11); Orn(A12); Orn(A13); Orn(A14); Orn(A15); Orn(A16); Orn(A17); Orn(A18); Orn(A19); Orn(A20); Orn(A21); Orn(A22); Orn(A23); Orn(A24); Orn(A25); Orn(A26); Orn(A27); Orn(A28); Orn(A29); Orn(A30); Orn(A31); Orn(A32); Orn(A33); Orn(A34); Orn(A35); Orn(A36); Orn(A37); Orn(A38); Orn(A39); Orn(A40); Orn(A41); Orn(A42); Orn(A43); Orn(A44); Orn(A45); Orn(A46); Orn(A47); Orn(A48); Orn(A49); Orn(A50); Orn(A51); Orn(A52); Orn(A53); Orn(A54); Orn(A55); Orn(A56); Asn(Alk1); Asn(Alk2); Asn(Alk3); Asn(Alk4); Asn(Alk5); Asn(Alk6); Asn(Alk7); Asn(Alk8); Asn(Alk9); Asn(Alk10); Asn(Alk11); Asn(Alk12); Asn(Alk13); Asn(Alk14); Asn(Alk15); Asn(Alk16); Asn(Alk17); Asn(Alk18); Asn(Alk19); Asn(Alk20); Asn(Alk21); Asn(Alk22); Asn(Alk23); Asn(Alk24); Asn(Alk25); Asn(Alk26); Asn(Alk27); Asn(Alk28); Asn(Alk29); Asn(Alk30); Asn(Alk31); Asn(Alk32); Asn(Alk33); Asn(Alk34); Asp(cN1); Asp(cN2); Asp(cN3); Asp(cN4); Asp(cN5); Asp(cN6); Asp(cN7); Asp(cN8); Asp(cN9); Asp(cN10); Asp(cN11); Asp(cN12); Asp(cN13); Asp(cN14); Asp(cN15); Asp(cN16); Asp(cN17); Dap(Ar1); Dap(Ar2); Dap(Ar3); Dap(Ar4); Dap(Ar5); Dap(Ar6); Dap(Ar7); Dap(Ar8); Dap(Ar9); Dap(Ar10); Dap(Ar11); Dap(Ar12); Dap(S1); Dap(S2); Dap(S3); Dap(S4); Dap(S5); Dap(S6); Dap(S7); Dap(S8); Dap(S9); Dap(S10); Dap(S11); Dap(S12); Dap(S13); Dap(S14); Dap(S15); Dap(S16); Dap(S17); Dap(S18); Dap(A1); Dap(A2); Dap(A3); Dap(A4); Dap(A5); Dap(A6); Dap(A7); Dap(A8); Dap(A9); Dap(A10); Dap(A11); Dap(A12); Dap(A13); Dap(A14); Dap(A15); Dap(A16); Dap(A17); Dap(A18); Dap(A19); Dap(A20); Dap(A21); Dap(A22); Dap(A23); Dap(A24); Dap(A25); Dap(A26); Dap(A27); Dap(A28); Dap(A29); Dap(A30); Dap(A31); Dap(A32); Dap(A33); Dap(A34); Dap(A35); Dap(A36); Dap(A37); Dap(A38); Dap(A39); Dap(A40); Dap(A41); Dap(A42); Dap(A43); Dap(A44); Dap(A45); Dap(A46); Dap(A47); Dap(A48); Dap(A49); Dap(A50); Dap(A51), Dap(A52); Dap(A53); Dap(A54); ou Dap(A55);
    P2 est DArg; DhArg; DAgb; DLys; DOrn; DCit; DThr; DDab; DDap; DPhe; DPhe(4CF3); DTrp; DHis; DTyr; D2Pal; D3Pal; D4Pal; DLys(Ar1); DLys(Ar2); DLys(Ar3); DLys(Ar4); DLys(Ar5); DLys(Ar6); DLys(Ar7); DLys(Ar8); DLys(Ar9); DLys(Ar10); DLys(Ar11); DLys(Ar12); DOrn(A41); DOrn(A56); DOrn(Ar1); DOrn(Ar2); DOrn(Ar3); DOrn(Ar4); DOrn(Ar5); DOrn(Ar6); DOrn(Ar7); DOrn(Ar8); DOrn(Ar9); DOrn(Ar10); DOrn(Ar11); DOrn(Ar12); DDab(Ar1); DDab(Ar2); DDab(Ar3); DDab(Ar4); DDab(Ar5); DDab(Ar6); DDab(Ar7); DDab(Ar8); DDab(Ar9); DDab(Ar10); DDab(Ar11); DDab(Ar12); DDap(Ar1); DDap(Ar2); DDap(Ar3); DDap(Ar4); DDap(Ar5); DDap(Ar6); DDap(Ar7); DDap(Ar8); DDap(Ar9); DDap(Ar10); DDap(Ar11); ou DDap(Ar12);
    et leurs sels pharmaceutiquement acceptables.
  4. Composés selon la revendication 1, dans lesquels
    T1 est DPro; DPip; DTic; DTiq; DOic; DAzt; DPro((3R)OH); DPro((3S)OH); DPro((3R)NH2); DPro((3S)NH2); DPro((4R)OH); DPro((4S)OH); DPro((4R)NH2); DPro((4S)NH2); DPro((4S)NHBz); ou DMor;
    T2 est Thr; alloThr; Ser; hSer; DPro((3R)OH); DPro((3S)OH); Hyp(Bn); (4S)-Hyp(Bn); Pro((3R)NH2); Pro((3S)NH2); Pro((4R)NH2); Pro((4S)NH2); Pro((4S)F); Pro((4S)NHBz); ou Mor; ou
    quand T1 est DPro((3R)OH); DPro((3S)OH); DPro((3R)NH2); DPro((3S)NH2); DPro((4R)NH2); DPro((4S)NH2); DPro((4S)NHBz); ou DMor
    alors T2 peut, en plus, être Pro; Pip; Tic; Tiq; Oic; ou Azt;
    p1 est Ile; Nle; Leu; Val; Chg; Cha; Abu; Ala; Ala(cPr); Ala(1Pyraz); Ala(Tet); Trp; 1Nal; 2Nal; Phe; Tyr; 2Pal; 3Pal; 4Pal; Thr; His; Arg; hArg; Agb; Pip; Orn(Ar2); ou Orn(A56);
    P2 est DArg; DhArg; DAgb; DLys; DOrn; DCit; DThr; DDab; DDap; DPhe; DTrp; DHis; DTyr; D2Pal; D3Pal; ou D4Pal;
    P3 est Arg; hArg; Agb; Agp; Lys; Orn; Orn(A41); Orn(A56); Orn(Ar2); Orn(Ar4); Orn(Ar7); Cit; Thr; Dab; Dap; Phe; Trp; His; Tyr; ou Ile;
    P4 est Trp; His; Phe; Phe(4CF3); 1Nal; 2Nal; Tyr; Leu; Ile; Arg; hArg; Lys; Dab; Dap; Orn; Orn(Ar56); ou Orn(Ar7);
    et leurs sels pharmaceutiquement acceptables.
  5. Composés selon la revendication 1, dans lesquels
    T1 est DPro; DPip; DTic; DPro((4S)OH); DPro((4R)NH2); ou DPro((4S)NH2);
    T2 est Thr; alloThr; Ser; hSer; DPro((3S)OH); (4S)-Hyp(Bn); Pro((4R)NH2); Pro((4S)NH2); Pro((4S)F); Pro((4S)NHBz); ou Mor;
    P1 est Ile; Nle; Leu; Val; Chg; Cha; Abu; Ala; Trp; 1Nal; Tyr; 3Pal; Thr; His; Arg; hArg; Agb; Pip; Ala(1Pyraz); Ala(Tet); Orn(Ar2); ou Orn(A56);
    P2 est DArg; DLys; DOrn; DCit; DThr; DDab; DPhe; DTrp; DHis; ou D3Pal;
    P3 est Arg; hArg; Agb; Agp; Lys; Orn; Orn(A41); Orn(A56); Orn(Ar2); Orn(Ar4); Orn(Ar7); Dab; Trp; ou His;
    P4 est Trp; His; Phe; Phe(4CF3); 1Nal; 2Nal; Tyr; Ile; Arg; hArg; Lys; Dab; Orn; Orn(Ar56); ou Orn(Ar7);
    et leurs sels pharmaceutiquement acceptables.
  6. Composés selon la revendication 1 choisis parmi :
    cyclo(-Ile-DArg-Arg-Ile-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Tyr-DPro-Thr-);
    cyclo(-Ile-DArg-Lys-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Dab-Trp-DPro-Thr-);
    cyclo(-Ile-DDab-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Phe-DPro-Thr-);
    cyclo(-Ile-DThr-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Trp-DPro-hSer-);
    cyclo(-Ile-DArg-Arg-Trp-DPro-alloThr-);
    cyclo(-1Nal-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DLys-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DHis-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DCit-Arg-Trp-DPro-Thr-);
    cyclo(-lle-DArg-Arg-Trp-DPip-Thr-);
    cyclo(-Ile-DArg-Arg-2Nal-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-1Nal-DPro-Thr-);
    cyclo(-Ile-DArg-Trp-Arg-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Thr-DArg-Trp-Arg-DPro-Thr-);
    cyclo(-Thr-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Trp-DPro-Pro((3S)OH)-);
    cyclo(-Ile-DArg-Arg-Trp-DPro-Ser-);
    cyclo(-Ile-DArg-Agp-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Agb-Trp-DPro-Thr-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro((4S)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Ala-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Tyr-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Orn-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Dab-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Lys-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-His-DPro((4R)NH2)-Tic-);
    cyclo(-Arg-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Pip-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-hArg-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Agb-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-3Pal-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-D3Pal-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Arg-DPhe-Trp-hArg-DPro((4R)NH2)-Tic-);
    cyclo(-Arg-DPhe-Trp-Arg-DPro((4S)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro((4R)NH2)-Oic-);
    cyclo(-Arg-DPhe-Trp-Arg-DPro((4R)NH2)-Oic-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro-Pro((4S)F)-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro-Pro((4S)NH2)-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro-Pro((4R)NH2)-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro-Mor-);
    cyclo(-Ile-DArg-Arg-Trp-DPro-Mor-);
    cyclo(-Arg-DPhe-Trp-Arg-DPro-(4S)Hyp(Bn)-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro((4S)OH)-(4S)Hyp(Bn)-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro((4R)NH2)-(4S)Hyp(Bn)-);
    cyclo(-His-DTrp-His-Trp-DPro-Pro((4S)NHBz)-);
    cyclo(-1Nal-DArg-Arg-Trp-DPro-Pro(3S)OH-);
    cyclo(-Ile-DArg-Arg-2Nal-DPro-Pro(3S)OH-);
    cyclo(-Ile-DArg-Arg-Trp-DPip-Pro((3S)OH)-);
    cyclo(-Ile-DArg-Arg-Trp-DPro(4S)OH-Thr-);
    cyclo(-Ile-DArg-Arg-Trp-DPro(4R)NH2-Thr-);
    cyclo(-Val-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Abu-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Chg-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Leu-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Nle-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Cha-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DOrn-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Orn(A41)-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Orn-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-hArg-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Trp-DTic-Thr-);
    cyclo(-Ile-DArg-Orn(Ar2)-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Orn(Ar7)-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Orn(Ar4)-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Orn(A56)-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Phe(4CF3)-DPro-Thr-);
    cyclo(-Trp-DPhe-Trp-Orn(A56)-DPip-Pro((3S)OH)-);
    cyclo(-Ala(1Pyraz)-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Ala(Tet)-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Orn(Ar2)-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Orn(A56)-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Orn(Ar7)-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Orn(A56)-DPro((4R)NH2)-Tiq-);
    cyclo(-Trp-DPhe-Trp-Orn(A56)-DPro((4R)NH2)-Tic-);
    et leurs sels pharmaceutiquement acceptables.
  7. Composés selon la revendication 6 choisis parmi :
    cyclo(-Ile-DArg-Arg-Trp-DPip-Thr-);
    cyclo(-Ile-DArg-Arg-2Nal-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Trp-DPro-Ser-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Dab-DPro((4R)NH2)-Tic-);
    cyclo(-3Pal-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro((4R)NH2)-Oic-);
    cyclo(-Trp-DPhe-Trp-Arg-DPro((4S)OH)-(4S)Hyp(Bn)-);
    cyclo(-Ile-DArg-Arg-Trp-DPip-Pro((3S)OH)-);
    cyclo(-Chg-DArg-Arg-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-hArg-Trp-DPro-Thr-);
    et leurs sels pharmaceutiquement acceptables.
  8. Composés selon la revendication 6 choisis parmi :
    cyclo(-Ile-DArg-Orn(Ar2)-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Orn(Ar7)-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Orn(Ar4)-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Orn(A56)-Trp-DPro-Thr-);
    cyclo(-Ile-DArg-Arg-Phe(4CF3)-DPro-Thr-);
    cyclo(-Trp-DPhe-Trp-Orn(A56)-DPip-Pro((3S)OH)-);
    cyclo(-Ala(1Pyraz)-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Ala(Tet)-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Orn(Ar2)-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Orn(Ar56)-DPhe-Trp-Arg-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Orn(Ar7)-DPro((4R)NH2)-Tic-);
    cyclo(-Trp-DPhe-Trp-Orn(A56)-DPro((4R)NH2)-Tiq-);
    cyclo(-Trp-DPhe-Trp-Orn(A56)-DPro((4R)NH2)-Tic-);
    et leurs sels pharmaceutiquement acceptables.
  9. Épimères et diastéréoisomères des composés selon la formule (I) comme défini dans la revendication 1 en fonction d'un ou plusieurs centres chiraux non-explicitement spécifiés dans la formule (I).
  10. Composés selon n'importe laquelle des revendications 1 à 9 pour utilisation comme substances thérapeutiquement actives, en particulier comme substances thérapeutiquement actives contre des maladies ou des troubles médiés ou subis par l'activité de CXCR7.
  11. Composés selon n'importe laquelle des revendications 1 à 9 ayant une activité modulatrice contre le récepteur CXCR7, en particulier interférant sélectivement avec l'activité naturelle du récepteur CXCR7 et ses ligands naturels CXCL11 et/ou CXCL12.
  12. Composition pharmaceutique contenant un composé ou un mélange de composés selon l'une quelconque des revendications 1 à 9 et un véhicule pharmaceutiquement inerte.
  13. Compositions selon la revendication 12 sous une forme adéquate pour administration orale, topique, transdermique, par injection, bucale, transmucosale, rectale, pulmonaire ou par inhalation, en particulier sous forme de comprimés, dragées, capsules, solutions, liquides, gels, emplâtres, crèmes, onguents, sirops, pâtes, suspensions, pulvérisations, nébulisations ou suppositoires.
  14. Utilisation de composés selon l'une quelconque des revendications 1 à 9 pour la fabrication d'un médicament comme unique ingrédient actif pharmaceutique ou en association avec d'autres ingrédients actifs pharmaceutiques.
  15. Utilisation de composés selon l'une quelconque des revendications 1 à 9 pour la fabrication d'un médicament pour le traitement, la prévention ou le traitement de soutien de maladies ou de troubles liés à l'activité de CXCR7 dans le domaine des troubles dermatologiques, troubles métaboliques, maladies inflammatoires, maladies fibreuses, maladies infectieuses, maladies neurologiques, maladies cardiovasculaires, maladies respiratoires, troubles du conduit gastro-intestinal, maladies urologiques, maladies des yeux, maladies stomatologiques, maladies hématologiques et oncologie, ou la mobilisation de cellules souches,
    en particulier pour la fabrication d'un médicament pour le traitement, la prévention ou le traitement de soutien de maladies ou de troubles tels que les infections au VIH, l'infection par le virus Eppstein-Barr; le diabètes sucré (type I et/ou type II); la conjonctivite, la sclérite, l'uvéite, la rhinosinusite, le syndrome WHIM, le lupus érythémateux, l'ostéoarthrite, l'arthrite rhumatoïde, la synovite, le psoriasis, la sclérose en plaques, la maladie de Crohn, la maladie inflammatoire chronique de l'intestin, la collagénose mixte, la thyroïdite chronique lymphocytaire, la maladie de Graves, la maladie du greffon contre l'hôte, la maladie de Sjögren, le syndrome de l'oeil sec, le glaucome, la dégénérescence maculaire liée à l'âge; l'hypertension artérielle pulmonaire, l'hypoxie pulmonaire, l'athérosclérose, la myocardite, une défaillance cardiaque, comme un infarctus du myocarde, la thrombose artérielle, l'attaque cérébrale, l'angiogénèse; la maladie pulmonaire obstructive chronique, la fibrose pulmonaire idiopathique, l'asthme; des sarcomes, comme l'ostéosarcome, le rhabdomyosarcome, le sarcome de Kaposi, le sarcome synovial; des lipomes, comme l'angliolipome; le glioblastome multiforme, les astrocytomes, les neuroblastomes; des carcinomes, comme l'adénocarcinome; des tumeurs malignes néoplasiques épithéliales et mucoépidermoïdes, des néoplasmes de la thyroïde, des néoplasmes gonadiques, le cancer de la prostate, le cancer des poumons, le mélanome, le carcinome pulmonaire, le carcinome pancréatique, le cancer colorectal; des tumeurs solides; des lymphomes, comme le lymphome de Birkitt, le lymphome de Hodgkin, les lymphomes non-hodgkiniens; le myélome multiple et la leucémie; des métastases; pour l'inhibition de la formation de néointima; pour la mobilisation de cellules souches issues des cellules souches du sang périphérique et/ou des cellules souches mésenchymales; pour la mobilisation de cellules progénitrices endothéliales ou neuronales; ou pour différents types de réparations de tissus chez l'être humain ou d'autres mammifères.
  16. Procédé de préparation de composés selon l'une quelconque des revendications 1 à 9, qui comprend :
    a) le couplage d'un support solide fonctionnalisé de façon adéquate avec un dérivé convenablement N-protégé de l'acide aminé qui, dans le produit final désiré, est en position T1 ou T2 ou P1 à P4 comme défini plus haut; tout groupe fonctionnel pouvant être présent dans ledit dérivé acide aminé N-protégé étant, de façon similaire, convenablement protégé;
    b) l'élimination du groupe N-protégé du produit obtenu à l'étape a);
    c) le couplage du produit ainsi obtenu avec un dérivé convenablement N-protégé de cet acide aminé qui, dans le produit final désiré, est dans la position de l'élément suivant (T ou P) en suivant dans le sens des aiguilles d'une montre ou dans le sens inverse des aiguilles d'une montre la séquence selon la formule générale (I) en orientation de -COOH vers -NH2; tout groupe fonctionnel pouvant être présent dans ledit dérivé acide aminé N-protégé étant, de façon similaire, convenablement protégé;
    d) l'élimination du groupe N-protégé du produit obtenu;
    e) la répétition des étapes c) et d) jusqu'à ce que tous les résidus acides aminés aient été introduits;
    f) si on le désire, la déprotection sélective d'un ou plusieurs groupes fonctionnels protégés présents dans la molécule et la substitution adéquate du ou des groupes réactifs ainsi libérés;
    g) le détachement du produit ainsi obtenu du support solide;
    h) la cyclisation du produit clivé du support solide;
    i) l'élimination de tout groupe protecteur présent sur les groupes fonctionnels de tout membre de la chaîne de résidus acides aminés et, si on le désire, de tout groupe protecteur qui puisse, en plus, être présent dans la molécule; et
    j) si on le désire, la mise en oeuvre de toute transformation chimique supplémentaire d'un ou plusieurs groupes réactifs présents dans la molécule;
    et/ou
    k) si on le désire, la conversion du produit ainsi obtenu en un sel pharmaceutiquement acceptable ou la conversion d'un sel pharmaceutiquement acceptable ou inacceptable ainsi obtenu en composé libre correspondant de formule (I) ou en un sel pharmaceutiquement acceptable différent.
EP11702229.3A 2010-02-05 2011-02-04 Peptidomimétiques fixés au brin matrice ayant une activité modulatrice des cxcr7 Not-in-force EP2531520B1 (fr)

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PCT/EP2010/051417 WO2011095218A1 (fr) 2010-02-05 2010-02-05 Peptidomimétiques fixés au brin matrice ayant une activité modulatrice des cxcr7
PCT/EP2011/051686 WO2011095607A1 (fr) 2010-02-05 2011-02-04 Peptidomimétiques fixés au brin matrice ayant une activité modulatrice des cxcr7
EP11702229.3A EP2531520B1 (fr) 2010-02-05 2011-02-04 Peptidomimétiques fixés au brin matrice ayant une activité modulatrice des cxcr7

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WO2007079597A1 (fr) 2006-01-16 2007-07-19 Polyphor Ltd. Peptidomimétiques à activité antimicrobienne fixés sur une matrice
EP2114986B1 (fr) 2007-01-29 2013-05-22 Polyphor Ltd. Peptidomimetiques fixes a une matrice
JP5140686B2 (ja) 2007-02-28 2013-02-06 ポリファー リミテッド テンプレート固定ペプチド模倣薬
US10815276B2 (en) 2014-05-21 2020-10-27 Entrada Therapeutics, Inc. Cell penetrating peptides and methods of making and using thereof
JP6807831B2 (ja) 2014-05-21 2021-01-06 エントラーダ セラピューティクス，インコーポレイテッド 細胞膜透過性ペプチド、並びにこの作製方法及び使用方法
EP3185880B1 (fr) 2014-08-27 2020-02-12 Ohio State Innovation Foundation Inhibiteurs améliorés de la peptidyl-calcineurine
WO2016046397A1 (fr) * 2014-09-25 2016-03-31 Servicio Andaluz De Salud Peptides cycliques contre la protéine membranaire externe a (ompa) pour le traitement d'infections provoquées par des pathogènes à gram négatif
EP3538157B1 (fr) 2016-11-10 2022-05-18 Ruprecht-Karls-Universität Peptides cycliques de piégeage du méthylglyoxal et leur utilisation pour la prévention et le traitement de maladies associées à des niveaux élevés de méthylglyoxal
WO2019148194A2 (fr) 2018-01-29 2019-08-01 Ohio State Innovation Foundation Inhibiteurs peptidyliques de l'interaction calcineurine-nfat
EP3755351A4 (fr) 2018-02-22 2021-11-24 Entrada Therapeutics, Inc. Compositions et méthodes de traitement de l'encéphalopathie mitochondriale neurogastro-intestinale
AR122446A1 (es) * 2020-04-29 2022-09-14 Medimmune Llc Composiciones y métodos para suministrar agentes farmacéuticamente activos

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DE10107707A1 (de) * 2001-02-19 2002-08-29 Wilex Biotechnology Gmbh Antagonisten für alpha¶4¶beta¶7¶-Integrin
GB0323728D0 (en) * 2003-10-10 2003-11-12 Royal College Of Surgeons Ie Peptidomimetics and uses thereof
EP2114986B1 (fr) 2007-01-29 2013-05-22 Polyphor Ltd. Peptidomimetiques fixes a une matrice
WO2011060832A1 (fr) * 2009-11-20 2011-05-26 Polyphor Ag Composés peptidomimétiques fixés sur une matrice et présentant une activité antagoniste du ccr10

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NZ601803A (en) 2014-04-30
SG183180A1 (en) 2012-09-27
CN102844327A (zh) 2012-12-26
US20150307556A1 (en) 2015-10-29
AU2011212412B2 (en) 2015-05-07
CA2789119A1 (fr) 2011-08-11
WO2011095218A1 (fr) 2011-08-11
CA2789119C (fr) 2020-01-28
JP2013518862A (ja) 2013-05-23
US9109009B2 (en) 2015-08-18
IL221316A (en) 2016-12-29
WO2011095607A1 (fr) 2011-08-11
IL221316A0 (en) 2012-10-31
AU2011212412A1 (en) 2012-08-30
US9637520B2 (en) 2017-05-02
JP5955780B2 (ja) 2016-07-20
EP2531520A1 (fr) 2012-12-12
CN102844327B (zh) 2016-10-26
US20130225506A1 (en) 2013-08-29

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